Mendelian randomization study on causal association of TEF and circadian rhythm with pulmonary arterial hypertension.

BACKGROUND: Previous research has revealed the potential impact of circadian rhythms on pulmonary diseases; however, the connection between circadian rhythm-associated Thyrotroph Embryonic Factor (TEF) and Pulmonary Arterial Hypertension (PAH) remains unclear. We aim to assess the genetic causal relationship between TEF and PAH by utilizing two sets of genetic instrumental variables (IV) and publicly available Pulmonary Arterial Hypertension Genome-Wide Association Studies (GWAS). METHODS: Total of 23 independent TEF genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. Gain- and loss-of-function experiments were used to demonstrate the role of TEF in PAH. RESULTS: Our analysis revealed that as TEF levels increased genetically, there was a corresponding increase in the risk of PAH, as evidenced by IVW (OR = 1.233, 95% CI: 1.054-1.441; P = 0.00871) and weighted median (OR = 1.292, 95% CI for OR: 1.064-1.568; P = 0.00964) methods. Additionally, the up-regulation of TEF expression was associated with a significantly higher likelihood of abnormal circadian rhythm (IVW: P = 0.0024733, ß = 0.05239). However, we did not observe a significant positive correlation between circadian rhythm and PAH (IVW: P = 0.3454942, ß = 1.4980398). In addition, our in vitro experiments demonstrated that TEF is significantly overexpressed in pulmonary artery smooth muscle cells (PASMCs). And overexpression of TEF promotes PASMC viability and migratory capacity, as well as upregulates the levels of inflammatory cytokines. CONCLUSION: Our analysis suggests a causal relationship between genetically increased TEF levels and an elevated risk of both PAH and abnormal circadian rhythm. Consequently, higher TEF levels may represent a risk factor for individuals with PAH.

The relativity analysis of hypoxia inducible factor-1α in pulmonary arterial hypertension (ascites syndrome) in broilers: a review.

Ascites syndrome (AS) in broiler chickens, also known as pulmonary arterial hypertension (PAH), is a significant disease in the poultry industry. It is a nutritional metabolic disease that is closely associated with hypoxia-inducible factors and rapid growth. The rise in pulmonary artery pressure is a crucial characteristic of AS and is instrumental in its development. Hypoxia-inducible factor 1α (HIF-1α) is an active subunit of a key transcription factor in the oxygen-sensing pathway. HIF-1α plays a vital role in oxygen homeostasis and the development of pulmonary hypertension. Studying the effects of HIF-1α on pulmonary hypertension in humans or mammals, as well as ascites in broilers, can help us understand the pathogenesis of AS. Therefore, this review aims to (1) summarize the mechanism of HIF-1α in the development of pulmonary hypertension, (2) provide theoretical significance in explaining the mechanism of HIF-1α in the development of pulmonary arterial hypertension (ascites syndrome) in broilers, and (3) establish the correlation between HIF-1α and pulmonary arterial hypertension (ascites syndrome) in broilers. HIGHLIGHTSExplains the hypoxic mechanism of HIF-1α.Linking HIF-1α to pulmonary hypertension in broilers.Explains the role of microRNAs in pulmonary arterial hypertension in broilers.

Unraveling the Impact of miR-146a in Pulmonary Arterial Hypertension Pathophysiology and Right Ventricular Function.

Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both hallmarks of PAH. This study aimed to investigate the effects of miR-146a through pharmacological or genetic inhibition on experimental PAH and RV pressure overload animal models. Additionally, we examined the overexpression of miR-146a on human pulmonary artery smooth muscle cells (hPASMCs). Here, we showed that miR-146a genic expression was increased in the lungs of patients with PAH and the plasma of monocrotaline (MCT) rats. Interestingly, genetic ablation of miR-146a improved RV hypertrophy and systolic pressures in Sugen 5415/hypoxia (SuHx) and pulmonary arterial banding (PAB) mice. Pharmacological inhibition of miR-146a improved RV remodeling in PAB-wild type mice and MCT rats, and enhanced exercise capacity in MCT rats. However, overexpression of miR-146a did not affect proliferation, migration, and apoptosis in control-hPASMCs. Our findings show that miR-146a may play a significant role in RV function and remodeling, representing a promising therapeutic target for RV hypertrophy and, consequently, PAH.

Advances in targeted therapy for pulmonary arterial hypertension in children.

Pulmonary arterial hypertension (PAH) is a rare and devastating disease of the pulmonary vasculature with a high morbidity and mortality rate in infants and children. Currently, treatment approaches are mostly based on adult guidelines and pediatrician clinical experience, focusing on specific pulmonary antihypertensive therapy and conventional supportive care. The advent of targeted drugs has led to significant advances in the treatment of PAH in children, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins, which have been studied and proven to improve hemodynamics and functional class in children PAH. A new targeted drug, riociguat, is assessing its safety and efficacy in clinical trials. However, more randomized controlled studies are needed to evaluate the combination of drugs, treatment strategies, and clinical endpoints of targeted therapy in children PAH. In this review, we summarize the research advances of PAH-targeted therapy in children over the last decade in order to provide a theoretical basis for future studies. CONCLUSION: Pulmonary arterial hypertension (PAH) is a rare and devastating pulmonary vascular disease that is associated with a variety of diseases of any age in childhood onset. WHAT IS KNOWN: • Therapeutic strategies for targeted drugs for PAH in children are based almost exclusively on data from adult studies and clinical experience of pediatric specialists. • Due to the complex etiology of PAH in children and the relative lack of clinical trial data, the selection of appropriate targeted drug therapy remains difficult. WHAT IS NEW: • We redefine the definition of pulmonary arterial hypertension in children and summarize the progress of targeted therapy of pulmonary arterial hypertension in children in the past ten years. • The dosage and adverse reactions were summarized, and the mechanism of action was drawn according to the available targeted drugs. It can provide theoretical support for the development of guidelines and treatment strategies for the diagnosis and treatment of pulmonary arterial hypertension in children.

The novel roles of YULINK in the migration, proliferation and glycolysis of pulmonary arterial smooth muscle cells: implications for pulmonary arterial hypertension.

BACKGROUND: Abnormal remodeling of the pulmonary vasculature, characterized by the proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) along with dysregulated glycolysis, is a pathognomonic feature of pulmonary arterial hypertension (PAH). YULINK (MIOS, Entrez Gene: 54468), a newly identified gene, has been recently shown to possess pleiotropic physiologic functions. This study aims to determine novel roles of YULINK in the regulation of PAH-related pathogenesis, including PASMC migration, proliferation and glycolysis. RESULTS: Our results utilized two PAH-related cell models: PASMCs treated with platelet-derived growth factor (PDGF) and PASMCs harvested from monocrotaline (MCT)-induced PAH rats (PAH-PASMCs). YULINK modulation, either by knockdown or overexpression, was found to influence PASMC migration and proliferation in both models. Additionally, YULINK was implicated in glycolytic processes, impacting glucose uptake, glucose transporter 1 (GLUT1) expression, hexokinase II (HK-2) expression, and pyruvate production in PASMCs. Notably, YULINK and GLUT1 were observed to colocalize on PASMC membranes under PAH-related pathogenic conditions. Indeed, increased YULINK expression was also detected in the pulmonary artery of human PAH specimen. Furthermore, YULINK inhibition led to the suppression of platelet-derived growth factor receptor (PDGFR) and the phosphorylation of focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K), and protein kinase B (AKT) in both cell models. These findings suggest that the effects of YULINK are potentially mediated through the PI3K-AKT signaling pathway. CONCLUSIONS: Our findings indicate that YULINK appears to play a crucial role in the migration, proliferation, and glycolysis in PASMCs and therefore positioning it as a novel promising therapeutic target for PAH.

Important Role of Endogenous Nerve Growth Factor Receptor in the Pathogenesis of Hypoxia-Induced Pulmonary Hypertension in Mice.

Pulmonary arterial hypertension (PAH) remains a disease with poor prognosis; thus, a new mechanism for PAH treatment is necessary. Circulating nerve growth factor receptor (Ngfr)-positive cells in peripheral blood mononuclear cells are associated with disease severity and the prognosis of PAH patients; however, the role of Ngfr in PAH is unknown. In this study, we evaluated the function of Ngfr using Ngfr gene-deletion (Ngfr-/-) mice. To elucidate the role of Ngfr in pulmonary hypertension (PH), we used Ngfr-/- mice that were exposed to chronic hypoxic conditions (10% O2) for 3 weeks. The development of hypoxia-induced PH was accelerated in Ngfr-/- mice compared to littermate controls. In contrast, the reconstitution of bone marrow (BM) in Ngfr-/- mice transplanted with wild-type BM cells improved PH. Notably, the exacerbation of PH in Ngfr-/- mice was accompanied by the upregulation of pulmonary vascular remodeling-related genes in lung tissue. In a hypoxia-induced PH model, Ngfr gene deletion resulted in PH exacerbation. This suggests that Ngfr may be a key molecule involved in the pathogenesis of PAH.

Systemic Lupus Erythematosus and Pulmonary Hypertension.

Pulmonary Hypertension (PH) is a common manifestation in patients with Systemic Lupus Erythematosus (SLE) and varies from asymptomatic to life-threatening disease. PH can result not only from immune system dysregulation, but also from various conditions, including cardiorespiratory disorders and thromboembolic diseases. Most commonly, SLE-related PH presents with non-specific symptoms, such as progressive dyspnea on exertion, generalized fatigue and weakness and eventually dyspnea at rest. Prompt diagnosis of SLE-related PH and early identification of the underlying pathogenetic mechanisms is demanded in order to introduce targeted therapy to prevent irreversible pulmonary vascular damage. In most cases the management of PH in SLE patients is similar to idiopathic pulmonary arterial hypertension (PAH). Furthermore, specific diagnostic tools like biomarkers or screening protocols, to establish early diagnosis seem to be not available yet. Although, the survival rates for patients with SLE-related PH vary between studies, it is evident that PH presence negatively affects the survival of SLE patients.

Soluble Guanylyl Cyclase Activators-Promising Therapeutic Option in the Pharmacotherapy of Heart Failure and Pulmonary Hypertension.

Endogenous nitric oxide (NO)-dependent vascular relaxation plays a leading role in the homeostasis of the cardiovascular, pulmonary, and vascular systems and organs, such as the kidneys, brain, and liver. The mechanism of the intracellular action of NO in blood vessels involves the stimulation of the activity of the soluble cytosolic form of guanylyl cyclase (soluble guanylyl cyclase, sGC), increasing the level of cyclic 3'-5'-guanosine monophosphate (cGMP) in smooth muscle and subsequent vasodilation. In recent years, a new group of drugs, soluble guanylyl cyclase stimulators, has found its way into clinical practice. Based on the CHEST-1 and PATENT-1 trials, riociguat was introduced into clinical practice for treating chronic thromboembolic pulmonary hypertension (CTEPH). In January 2021, the FDA approved the use of another drug, vericiguat, for the treatment of heart failure.

Scleroderma hypertensive renal crisis among systemic sclerosis patients: A national emergency department database study.

BACKGROUND: Literature regarding trends for incidence and mortality of scleroderma renal crisis (SRC) in systemic sclerosis (SSc) within the United States (US) emergency departments (EDs) is limited. OBJECTIVE: To study the mortality of SRC among SSc patient encounters within the US EDs. METHODS: Data from the National Emergency Department Sample (NEDS) constitutes 20% sample of hospital-owned EDs and inpatient sample in the US were analyzed for SSc with and without SRC using ICD-9 codes. A linear p-trend was used to assess the trends. RESULTS: Of the total 180,435 encounters with the diagnosis of SSc in NEDS for the years 2009 2014, 771 or 4.27/1000 patients (mean age 59.6 ± 15.5 years, 75.4% females) were recorded with SRC. The numerical differences in mortality among SRC (32 or 4.1%) and non-SRC subgroups (5487 or 3.1%) did not reach statistical significance (p = 0.3). Major complications among SRC in comparison to non-SRC subgroup include ischemic stroke (5.6% vs 0.98%, p = 0.001), new-onset AF (8% vs 6.9%, p = 0.001), new-onset congestive heart failure (24.1% vs 8.8%, p = 0.001), pulmonary arterial hypertension (15.8% vs 10.9%, p = 0.001), respiratory failure (27.5% vs 10.5%, p = 0.001), and deep vein thrombosis (4.7% vs 4.6%, p = 0.001). Congestive heart failure (CHF) was strongly associated with SRC among SSc (OR 4.3 95%CI 2.7-6.7; p < 0.001). The absolute yearly rate of SRC had increased over the study years from 2.11/1000 to 5.79/1000 (linear p-trend 0.002) while the mortality trend remained steady. CONCLUSION: SRC is a relatively rare medical emergency. Although there has been a significant rise in the rate of SRC among SSc patients over the study years, mortality rates had remained steady. SSc patients with CHF should be considered to have low threshold for admission to inpatient services from EDs.

NAADP-induced intracellular calcium ion is mediated by the TPCs (two-pore channels) in hypoxia-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a form of obstructive vascular disease. Chronic hypoxic exposure leads to excessive proliferation of pulmonary arterial smooth muscle cells and pulmonary arterial endothelial cells. This condition can potentially be aggravated by [Ca2+ ] i mobilization. In the present study, hypoxia exposure of rat's model was established. Two-pore segment channels (TPCs) silencing was achieved in rats' models by injecting Lsh-TPC1 or Lsh-TPC2. The effects of TPC1/2 silencing on PAH were evaluated by H&E staining detecting pulmonary artery wall thickness and ELISA assay kit detecting NAADP concentrations in lung tissues. TPC1/2 silencing was achieved in PASMCs and PAECs, and cell proliferation was detected by MTT and BrdU incorporation assays. As the results shown, NAADP-activated [Ca2+ ]i shows to be mediated via two-pore segment channels (TPCs) in PASMCs, with TPC1 being the dominant subtype. NAADP generation and TPC1/2 mRNA and protein levels were elevated in the hypoxia-induced rat PAH model; NAADP was positively correlated with TPC1 and TPC2 expression, respectively. In vivo, Lsh-TPC1 or Lsh-TPC2 infection significantly improved the mean pulmonary artery pressure and PAH morphology. In vitro, TPC1 silencing inhibited NAADP-AM-induced PASMC proliferation and [Ca2+ ]i in PASMCs, whereas TPC2 silencing had minor effects during this process; TPC2 silencing attenuated NAADP-AM- induced [Ca2+ ]i and ECM in endothelial cells, whereas TPC1 silencing barely ensued any physiological changes. In conclusion, TPC1/2 might provide a unifying mechanism within pulmonary arterial hypertension, which can potentially be regarded as a therapeutic target.

TRIM32 inhibits the proliferation and migration of pulmonary artery smooth muscle cells through the inactivation of PI3K/Akt pathway in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive and fetal cardiovascular disease. Tripartite motif 32 (TRIM32) is a member of TRIM family that has been found to be involved in cardiovascular disease. However, the role of TRIM32 in PAH remains unclear. Here we investigated the effects of TRIM32 on hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) in vitro. Our results showed that TRIM32 protein level in the plasma samples from PAH patients was decreased as compared with healthy volunteers. Exposure to hypoxia condition caused a significant decrease in TRIM32 expression in PASMCs. Overexpression of TRIM32 inhibited hypoxia-induced proliferation and migration of PASMCs. TRIM32 overexpression elevated the increased apoptotic rate and caspase-3 activity in hypoxia-induced PASMCs. Moreover, overexpression of TRIM32 reversed hypoxia-induced down-regulation of myocardin, SM 22 and calponin, as well as up-regulation of osteopontin (OPN). Whereas, TRIM32 knockdown shwed the opposite effect. Furthermore, overexpression of TRIM32 inhibited hypoxia-induced activation of PI3K/Akt with decreased phosphorylated level of PI3K and Akt. Additionally, activation of PI3K/Akt by IGF-1 treatment reversed the effects of TRIM32 on hypoxia-induced PASMCs. In conclusion, these findings indicated that TRIM32 was involved in the development of PAH through regulating the proliferation, migration, apoptosis and dedifferentiation of PASMCs, which might be mediated by the PI3K/Akt signaling pathway. Thus, TRIM32 might be a potential target for PAH treatment.

Monotherapy in patients with pulmonary arterial hypertension at four German PH centres.

BACKGROUND: Although combination therapy is the gold standard for patients with pulmonary arterial hypertension (PAH), some of these patients are still being treated with monotherapy. METHODS: We conducted a retrospective analysis at four German PH centres to describe the prevalence and characteristics of patients receiving monotherapy. RESULTS: We identified 131 incident PAH patients, with a mean age of 64 ± 13.8 years and a varying prevalence of comorbidities, cardiovascular risk factors and targeted therapy. As in other studies, the extent of prescribed PAH therapy varied with age and coexisting diseases, and younger, so-called "typical" PAH patients were more commonly treated early with combination therapy (48% at 4-8 months). In contrast, patients with multiple comorbidities or cardiovascular risk factors were more often treated with monotherapy (69% at 4-8 months). Survival at 12 months was not significantly associated with the number of PAH drugs used (single, dual, triple therapy) and was not different between "atypical" and "typical" PAH patients (89% vs. 85%). CONCLUSION: Although "atypical" PAH patients with comorbidities or a more advanced age are less aggressively treated with respect to combination therapy, the outcome of monotherapy in these patients appears to be comparable to that of dual or triple therapy in "typical" PAH patients.

Current Modulation of Guanylate Cyclase Pathway Activity-Mechanism and Clinical Implications.

For years, guanylate cyclase seemed to be homogenic and tissue nonspecific enzyme; however, in the last few years, in light of preclinical and clinical trials, it became an interesting target for pharmacological intervention. There are several possible options leading to an increase in cyclic guanosine monophosphate concentrations. The first one is related to the uses of analogues of natriuretic peptides. The second is related to increasing levels of natriuretic peptides by the inhibition of degradation. The third leads to an increase in cyclic guanosine monophosphate concentration by the inhibition of its degradation by the inhibition of phosphodiesterase type 5. The last option involves increasing the concentration of cyclic guanosine monophosphate by the additional direct activation of soluble guanylate cyclase. Treatment based on the modulation of guanylate cyclase function is one of the most promising technologies in pharmacology. Pharmacological intervention is stable, effective and safe. Especially interesting is the role of stimulators and activators of soluble guanylate cyclase, which are able to increase the enzymatic activity to generate cyclic guanosine monophosphate independently of nitric oxide. Moreover, most of these agents are effective in chronic treatment in heart failure patients and pulmonary hypertension, and have potential to be a first line option.

Diagnosis and Management of Pulmonary Hypertension in Patients With CKD.

Pulmonary hypertension (PH) is a highly prevalent and important condition in adults with chronic kidney disease (CKD). In this review, we summarize the definition of PH, discuss its pathophysiology and classifications, and describe diagnostic and management strategies in patients with CKD, including those with kidney failure treated by kidney replacement therapy. In the general population, PH is classified into 5 groups based on clinical presentation, pathology, hemodynamics, and management strategies. In this classification system, PH in CKD is placed in a diverse group with unclear or multifactorial mechanisms, although underlying cardiovascular disease may account for most cases. CKD may itself directly incite pulmonary circulatory dysfunction and remodeling through uremic toxins, inflammation, endothelial dysfunction, and altered vasoregulation. Despite several studies describing the higher prevalence of PH in CKD and kidney failure, along with an association with poor outcomes, high-quality evidence is not available for its diagnostic and management strategies in those with CKD. In CKD not requiring kidney replacement therapy, volume management along with treatment of underlying risk factors for PH are critical. In those receiving hemodialysis, options are limited and transition to peritoneal dialysis may be considered if recurrent hypotension precludes optimal volume control.

Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterised by an increase in mean pulmonary arterial pressure which almost invariably leads to right heart failure and premature death. More than 70% of familial PAH and 20% of idiopathic PAH patients carry heterozygous mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2). However, the incomplete penetrance of BMPR2 mutations suggests that other genetic and environmental factors contribute to the disease. In the current study, we investigate the contribution of autophagy in the degradation of BMPR2 in pulmonary vascular cells. We demonstrate that endogenous BMPR2 is degraded through the lysosome in primary human pulmonary artery endothelial (PAECs) and smooth muscle cells (PASMCs): two cell types that play a key role in the pathology of the disease. By means of an elegant HaloTag system, we show that a block in lysosomal degradation leads to increased levels of BMPR2 at the plasma membrane. In addition, pharmacological or genetic manipulations of autophagy allow us to conclude that autophagy activation contributes to BMPR2 degradation. It has to be further investigated whether the role of autophagy in the degradation of BMPR2 is direct or through the modulation of the endocytic pathway. Interestingly, using an iPSC-derived endothelial cell model, our findings indicate that BMPR2 heterozygosity alone is sufficient to cause an increased autophagic flux. Besides BMPR2 heterozygosity, pro-inflammatory cytokines also contribute to an augmented autophagy in lung vascular cells. Furthermore, we demonstrate an increase in microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) levels in lung sections from PAH induced in rats. Accordingly, pulmonary microvascular endothelial cells (MVECs) from end-stage idiopathic PAH patients present an elevated autophagic flux. Our findings support a model in which an increased autophagic flux in PAH patients contributes to a greater decrease in BMPR2 levels. Altogether, this study sheds light on the basic mechanisms of BMPR2 degradation and highlights a crucial role for autophagy in PAH. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

COVID-19 in a Patient with ß-Thalassemia Major and Severe Pulmonary Arterial Hypertension.

We here report the successful recovery from coronavirus disease-19 (COVID-19) pneumonia in a patient with ß-thalassemia major (ß-TM) and severe pulmonary arterial hypertension (PAH), focusing on the patient's comorbidities, therapeutic course and drug interaction.

MnTBAP Reverses Pulmonary Vascular Remodeling and Improves Cardiac Function in Experimentally Induced Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by obstructed pulmonary vasculatures. Current therapies for PAH are limited and only alleviate symptoms. Reduced levels of BMPR2 are associated with PAH pathophysiology. Moreover, reactive oxygen species, inflammation and autophagy have been shown to be hallmarks in PAH. We previously demonstrated that MnTBAP, a synthetic metalloporphyrin with antioxidant and anti-inflammatory activity, inhibits the turn-over of BMPR2 in human umbilical vein endothelial cells. Therefore, we hypothesized that MnTBAP might be used to treat PAH. Human pulmonary artery endothelial cells (PAECs), as well as pulmonary microvascular endothelial (MVECs) and smooth muscle cells (MVSMCs) from PAH patients, were treated with MnTBAP. In vivo, either saline or MnTBAP was given to PAH rats induced by Sugen 5416 and hypoxia (SuHx). On PAECs, MnTBAP was found to increase BMPR2 protein levels by blocking autophagy. Moreover, MnTBAP increased BMPR2 levels in pulmonary MVECs and MVSMCs isolated from PAH patients. In SuHx rats, MnTBAP reduced right ventricular (RV) afterload by reversing pulmonary vascular remodeling, including both intima and media layers. Furthermore, MnTBAP improved RV function and reversed RV dilation in SuHx rats. Taken together, these data highlight the importance of MnTBAP as a potential therapeutic treatment for PAH.

alpha1A-adrenoceptor is involved in norepinephrine-induced proliferation of pulmonary artery smooth muscle cells via CaMKII signaling.

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Some studies have demonstrated the sympathetic nervous system is activated in PAH and norepinephrine (NE) released is closely linked with its activation. However, the subtypes of adrenoreceptor (AR) and the downstream molecular cascades which are involved in the proliferation of PASMCs are still unclear. In this study, adult male Wistar rats were exposed to chronic hypoxia and PASMCs were cultured in hypoxic condition. Significant upregulation of α1A -AR was identified by Western blot analysis or immunofluorescence in all of the pulmonary arteries, lung tissues, and cell hypoxic models. Western blot analysis, flow cytometry, and immunofluorescence were applied to detect the roles of α1A -AR in NE mediated proliferation of PASMCs. We revealed 5-methylurapidil (5-MU) reversed NE-induced upregulation of PCNA, CyclinA and CyclinE, more cells from G0 /G1 phase to G2 /M+S phase, enhancement of the microtubule formation. In addition, we found calcium/calmodulin(CaM)-dependent protein kinase type II (CaMKII) pathway was involved in α1A -AR-mediated cell proliferation. [Ca2+ ]i measurements showed that an increase of [Ca2+ ]i caused by NE or/and hypoxia could be blocked by 5-MU in PASMCs. Western blot analysis results demonstrated the augmentation of CaMKII phosphorylation level was caused by hypoxia or NE in pulmonary arteries, lung tissues, and PASMCs. KN62 attenuated NE-induced proliferation of PASMCs under normoxia and hypoxia. In conclusion, those results suggested NE which stimulated α1A -AR-mediated the proliferation of PASMCs, which may be via the CaMKII pathway, and it could be used as a novel treatment strategy in PAH.

In-silico assessment of the effects of right ventricular assist device on pulmonary arterial hypertension using an image based biventricular modeling framework.

Pulmonary arterial hypertension (PAH) is a heart disease that is characterized by an abnormally high pressure in the pulmonary artery (PA). While right ventricular assist device (RVAD) has been considered recently as a treatment option for the end-stage PAH patients, its effects on biventricular mechanics are, however, largely unknown. To address this issue, we developed an image-based modeling framework consisting of a biventricular finite element (FE) model that is coupled to a lumped model describing the pulmonary and systemic circulations in a closed-loop system. The biventricular geometry was reconstructed from the magnetic resonance images of two PAH patients showing different degree of RV remodeling and a normal subject. The framework was calibrated to match patient-specific measurements of the left ventricular (LV) and RV volume and pressure waveforms. An RVAD model was incorporated into the calibrated framework and simulations were performed with different pump speeds. Results showed that RVAD unloads the RV, improves cardiac output and increases septum curvature, which are more pronounced in the PAH patient with severe RV remodeling. These improvements, however, are also accompanied by an adverse increase in the PA pressure. These results suggest that the RVAD implantation may need to be optimized depending on disease progression.

Frequency and predictors of pulmonary hypertension in patients with Systemic Lupus Erythematosus.

OBJECTIVE: To determine the frequency and predictors of pulmonary hypertension in patients with Systemic Lupus Erythematosus in a Pakistani population, presenting at a tertiary care hospital. METHODS: This cross-sectional study was conducted at the Department of Rheumatology, Shiekh Zayed Hospital, Lahore from March to June 2018. A total of 97 patients, who fulfilled the Systemic Lupus Erythematosus (SLE) criteria of American College of Rheumatology (ACR) 1992 were enrolled. Pulmonary Arterial Hypertension (PAH) was measured by calculating pulmonary arterial systolic pressure through echocardiography by a single consultant cardiologist. Disease characteristics and demography was collected in a self-administered proforma. PAH was defined as mean pulmonary arterial pressure of 25mmHg or above by calculating with a formula. SPSS version 20 was used for analysis of data. RESULTS: Out of 97 patients, 89.7% (n=87) were females and 10.3% (n=10) were males, with mean age of 31.29± 8.824 years. The mean disease duration was 24.21 ± 30.46 months. PAH was found in 23.3% (n=23) patients, including 19 females and 4 males. On further analysis of data, Raynaud phenomenon, rheumatoid factor and nephritis were assessed as predictors of PAH and all of these showed statistical significance for presence of PAH as per Chi-square test (p<0.05). CONCLUSION: In this study, 23.3% SLE patients showed evidence of PAH and positive statistical significance was found between predictors like Raynaud phenomenon, rheumatoid factor, nephritis and presence of PAH. So it is imperative to detect PAH early and start prompt treatment to achieve better quality of life.